title: Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington's disease.
abstract: Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development.
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fisher
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Black
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schwartz
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wilk
authors.forename: Tsui-Ming
authors.initials: TM
authors.lastname: Chen
authors.forename: Webster U
authors.initials: WU
authors.lastname: Lincoln
authors.forename: Helen W
authors.initials: HW
authors.lastname: Liu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Morairty
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000235:genetics; D058256:Brain Waves / Q000235:genetics / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004569:Electroencephalography; D004576:Electromyography; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D012892:Sleep Deprivation / Q000503:physiopathology; D012894:Sleep Stages / Q000235:genetics / Q000502:physiology*; D012893:Sleep Wake Disorders / Q000209:etiology*; D013057:Spectrum Analysis; D018911:Trinucleotide Repeats / Q000235:genetics; D014851:Wakefulness / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins
keywords: EEG; Huntington’s disease; R6/2 transgenic mice; biomarkers; sleep